Ver­sant care­ful­ly sets the stage for a $68M de­but of a biotech play­er fo­cused on syn­thet­ic lethal­i­ty

Over the past 18 months, the grow­ing team at Re­pare Ther­a­peu­tics has been qui­et­ly set­ting up shop in Ver­sant Ven­tures’ dis­cov­ery ops and fo­cus­ing on syn­thet­ic lethal­i­ty — the ther­a­peu­tic in­ter­play be­tween ge­net­ic mu­ta­tions and can­cer. Us­ing CRISPR gene edit­ing tech as an in­ter­ro­ga­tion tool, they’ve been play­ing with well known tar­gets like p53 and BR­CA1 to find out how they con­spire with oth­er mu­ta­tions in the de­struc­tion of a ma­lig­nan­cy, fol­low­ing the trail of le­sions in the pur­suit of new ther­a­pies that can work in the same fun­da­men­tal way those PARP in­hibitors you’ve been hear­ing so much about can fight can­cer.

The goal was to mas­ter syn­thet­ic lethal­i­ty and iden­ti­fy the first cou­ple of tar­gets to go af­ter in the clin­ic. They lined up their team, now at 20, li­censed in dis­cov­ery work from NYU on a poly­merase im­pli­cat­ed in nu­mer­ous can­cers, and to­day will come out of stealth mode with a $68 mil­lion round and at least a four-year run­way with plans to start tack­ling clin­i­cal work in late 2019.

Their first pro­gram in­volves DNA-di­rect­ed DNA poly­merase theta — PolQ — in­clud­ed in a path­way that re­pairs dou­ble-strand breaks in can­cer cells. And while they have a ways to go be­fore they be­gin hu­man stud­ies, the in­vestors are send­ing a mes­sage that the amount of cash they’re bet­ting on Re­pare in­di­cates a high lev­el of con­fi­dence for their longterm suc­cess.

Jer­el Davis

“In terms of the in­cu­ba­tion pe­ri­od,” says Jer­el Davis, man­ag­ing di­rec­tor at Ver­sant, “this com­pa­ny is de­cep­tive­ly ma­ture.”

“The time we’ve been able to spend in stealth al­lowed us to build the com­pa­ny out of the spot­light,” says CEO Lloyd Se­gal. In Mon­tre­al they have de­vel­oped their med­i­c­i­nal chem­istry team un­der Cameron Black, the for­mer head of chem­istry at Mer­ck Frosst who joined a lit­tle more than a year ago. And when Ver­tex re­cent­ly shut down in Mon­tre­al, they swooped in, grab­bing an ex­pe­ri­enced team with a long track record of work­ing to­geth­er.

Lloyd Se­gal

With­in hours of the shut­down, they had 13 new re­cruits out of 14 of­fers.

R&D head Michael Zin­da, who led As­traZeneca On­col­o­gy iMed Bio­science group in Boston, is head­ing up the oth­er group in Cam­bridge, MA.

Ver­sant has gath­ered an im­pres­sive group of mar­quee in­vestors to back their up­start. MPM Cap­i­tal came in along­side as the lead in­vestor on the Se­ries A, with Cel­gene’s Swiss of­fice tak­ing part along with FTQ and BDC Ven­tures.

“We could have tak­en more mon­ey,” Se­gal tells me. “We had more than that on the ta­ble. But we be­lieved that was the kind of mon­ey that we hope will take two com­pounds in­to the clin­ic in late ’19 or ear­ly 2020.”

Ver­sant had a front row seat on some of the ear­ly work on syn­thet­ic lethal­i­ty at Clo­vis while it was work­ing on PARP, says Davis. “This is a field we know and our con­vic­tion is that PARP is the tip off the ice­berg.”

Re­pare has the plat­form that they plan to use to map out some of the rest of the un­ex­plored ter­ri­to­ry.

Even with­out R&D part­ners Se­gal feels that he has enough cash to make their way through at least the first 4 years. Add in the prospect of some ma­jor league play­ers com­ing in to part­ner on key prospects, and that run­way will stretch fur­ther. If it all plays out ac­cord­ing to plan, Se­gal adds, this will be their last ven­ture raise.

It’s an am­bi­tious plan, with some stel­lar sci­en­tif­ic ad­vis­ers ready to leaned guid­ance. The full sci­en­tif­ic ad­vi­so­ry board in­cludes:

– Samuel Apari­cio, pro­fes­sor in the de­part­ment of pathol­o­gy and lab­o­ra­to­ry med­i­cine at the Uni­ver­si­ty of British Co­lum­bia.

– Jim Carmichael, head of the pro­tein home­osta­sis the­mat­ic cen­ter of ex­cel­lence at Cel­gene. He pre­vi­ous­ly was UK re­gion­al di­rec­tor of med­ical sci­ence at As­traZeneca fol­low­ing its ac­qui­si­tion of Ku­DOS, where he was CMO and re­spon­si­ble for clin­i­cal de­vel­op­ment of ola­parib.

– Ron­ny Drap­kin, di­rec­tor of the Penn Ovar­i­an Can­cer Re­search Cen­ter and di­rec­tor of gy­ne­co­log­ic can­cer re­search at the Uni­ver­si­ty of Penn­syl­va­nia.

– Lau­rie Glim­ch­er, pres­i­dent and CEO of the Dana-Far­ber Can­cer In­sti­tute.

– Mark Pe­gram, di­rec­tor of the breast can­cer on­col­o­gy pro­gram at Stan­ford Women’s Can­cer Cen­ter and co-di­rec­tor of Stan­ford’s mol­e­c­u­lar ther­a­peu­tics pro­gram.

– Richard Wood, pro­fes­sor of mol­e­c­u­lar bi­ol­o­gy at the Uni­ver­si­ty of Texas MD An­der­son Can­cer Cen­ter.

Con­quer­ing a silent killer: HDV and Eiger Bio­Phar­ma­ceu­ti­cals

Hepatitis delta, also known as hepatitis D, is a liver infection caused by the hepatitis delta virus (HDV) that results in the most severe form of human viral hepatitis for which there is no approved therapy.

HDV is a single-stranded, circular RNA virus that requires the envelope protein (HBsAg) of the hepatitis B virus (HBV) for its own assembly. As a result, hepatitis delta virus (HDV) infection occurs only as a co-infection in individuals infected with HBV. However, HDV/HBV co-infections lead to more serious liver disease than HBV infection alone. HDV is associated with faster progression to liver fibrosis (progressing to cirrhosis in about 80% of individuals in 5-10 years), increased risk of liver cancer, and early decompensated cirrhosis and liver failure.
HDV is the most severe form of viral hepatitis with no approved treatment.
Approved nucleos(t)ide treatments for HBV only suppress HBV DNA, do not appreciably impact HBsAg and have no impact on HDV. Investigational agents in development for HBV target multiple new mechanisms. Aspirations are high, but a functional cure for HBV has not been achieved nor is one anticipated in the forseeable future. Without clearance of HBsAg, anti-HBV investigational treatments are not expected to impact the deadly course of HDV infection anytime soon.

UP­DAT­ED: In a land­mark first glimpse of hu­man da­ta from Ver­tex, CRISPR/Cas9 gene ther­a­py sig­nals ear­ly ben­e­fit

Preliminary data on two patients with blood disorders that have been administered with Vertex and partner CRISPR Therapeutics’ gene-editing therapy suggest the technology is safe and effective, marking the first instance of the benefit of the use of CRISPR/Cas9 technology in humans suffering from disease.

Patients in these phase I/II studies give up peripheral blood from which hematopoietic stem and progenitor cells are isolated. The cells are tinkered with using CRISPR/Cas9 technology, and the edited cells — CTX001 — are infused back into the patient via a stem cell transplant. The objective of CTX001 is to fix the errant hemoglobin gene in patents with two blood disorders: beta-thalassemia and sickle cell disease, by unleashing the production of fetal hemoglobin.

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UP­DAT­ED: Make that 2 ap­proved RNAi drugs at Al­ny­lam af­ter the FDA of­fers a speedy OK on ul­tra-rare dis­ease drug

Seventeen years into the game, Alnylam’s pivot into commercial operations is picking up speed.
The bellwether biotech $ALNY has nabbed their second FDA OK for an RNAi drug, this time for givosiran, the only therapy now approved for acute hepatic porphyria. This second approval came months ahead of the February deadline — even after winning priority review following their ‘breakthrough’ title earlier.
AHP is an extremely rare disease, with some 3,000 patients in Europe and the US, not all diagnosed, and analysts have projected peak revenue of $600 million to $700 million a year. The drug will be sold as Givlaari.

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David Ricks. Eli Lilly

Eli Lil­ly touts $400M man­u­fac­tur­ing ex­pan­sion, 100 new jobs to much fan­fare in In­di­anapo­lis — even though it's been chop­ping staff

Eli Lilly is pouring in $400 million to beef up manufacturing facilities at its home base of Indianapolis. The investment, which was lauded by the city’s mayor, is expected to create 100 new jobs.

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Am­gen chops 172 more staffers in R&D, op­er­a­tions and sales amid neu­ro­science ex­it, rev­enue down­turn

Neuroscience wasn’t the only unit that’s being hit by a reorganization underway at Amgen. As well as axing 149 employees in its Cambridge office, the company has disclosed that 172 others nationwide, including some from its Thousand Oaks, CA headquarters, are being let go.

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Stephen Hahn (via Senate HELP Committee)

Stephen Hahn gets through Sen­ate’s soft­ball job in­ter­view — but most­ly plays dodge­ball on the is­sues fac­ing the FDA

Anyone looking for fresh insights on what kind of FDA commissioner Stephen Hahn will be got precious few clues during Wednesday’s Senate hearing on the nomination.

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Op­di­vo/Yer­voy com­bo for melanoma fails in key pa­tient pop­u­la­tion

Bristol-Myers Squibb’s efforts to expand their checkpoint inhibitor combination have run into another recalcitrant cancer.

The NJ-based pharma announced that a combination of Yervoy and Opdivo didn’t beat out Opdivo alone in patients with resected high-risk melanoma who had very low levels of PD-L1. The drug combo couldn’t improve recurrence-free survival in these post-surgery patients.

Ver­tex's stel­lar quar­ter car­ries on with French re­im­burse­ment deal

Vertex’s golden quarter just got brighter. About a month after the US drugmaker finally clinched a deal with UK authorities to cover its slate of cystic fibrosis (CF) drugs following years of protracted negotiations, the company on Wednesday secured a deal with France for its CF therapy, Orkambi.

After the UK, France has one of the largest CF populations outside the United States. Achieving French reimbursement unlocks an ~7000-patient CF population, around ~2500-3000 of which will likely be eligible to receive (and be reimbursed for) Orkambi, Stifel’s Paul Matteis wrote in a note.

Nello Mainolfi, Kymera via Youtube

Kymera hands the helm to No­var­tis vet — and found­ing CSO — Nel­lo Main­olfi

Kymera Therapeutics is turning to a co-founder to run the company.
The protein degradation specialist with a deep-pocket syndicate behind them has opted to give the helm officially to Nello Mainolfi. The new CEO is a veteran of the Novartis Institutes for Biomedical Research. He joined Atlas Venture in their entrepreneur-in-residence program and helped launch Kymera as the CSO three years ago with Atlas’ Bruce Booth.
The boast at Kymera is that they’re angling to create a new class of protein degraders, a popular field where there’s been a variety of startups. One of its chief advocates is NIBR head Jay Bradner, who launched C4 just ahead of joining Novartis, where he’s also been doing new work in the field.